Tests carried out in the past few years have revealed that thymus hormones directly participate in processes regulating the T-lymphocyte-dependent immunological equilibrium. They appear to convert the young T-cells into ripe, differentiated cells which have a central role in cell-mediated immunity and in the regulation of various immune responses. The thymus hormones exert their activity not only inside but also outside the thymus and play a role in the formation of cytotoxic, supressant and helper cells. The promising results of the first clinical tests carried out by thymus extracts on patients suffering from immune deficiency or cancer gave a further impulse to the research activity in this field. It has further been revealed that in the case of DiGeorge syndrome, IgA deficiency and general skin tuberculosis the thymus level of the serum decreases while in the case of rheumatoid arthritis the increase of thymus level has been observed. It can, therefore, reasonably be concluded that the regulation of the hormone level will have a favorable influence on these diseases [E. Arrigoni-Martelli: Drugs of Today 16, 203 (1980)].
One of the thymus hormones which has been isolated as a uniform product, structurally identified and even synthesized is thymopoietine [Goldstein et al: Nature 247, 11 (1974); Goldstein et al: Ann. N. Y. Sci. 249, 177 (1975); U.S. Pat. Nos. 4,002,740 and 4,077,949] consisting of 49 amino acids. Tests carried out with the natural and then the synthetic product [Fujino et al: Chem. Pharm. Bull. 25, 1486 (1977); Bliznakov et al: Biochem. Biophys. Res. Commun. 80, 631 (1978)] unambiguously show that thymopoietine induces the differentiation of the T-cells in vitro and in vivo as well.
Due to the restricted natural resources of thymopoietine which are not sufficient to meet the great demands and the high price of the synthetic product an extensive research activity has been initiated to determine the active center of thymopoietine. At first a tridecapeptide, thymopoietine(24-41) [Schlesinger et al: Cell 5, 631 (1978)] and then a pentapeptide, thymopoietine(32-36) (designated as TP5) were reported to possess all biological properties of the complete hormone [Goldstein et al: Science 204, 1309 (1979); U.S. Pat. No. 4,190,646]. Recently certain fragments and analogs of TP5 have also been described which were, however, ineffective in the test system [Abiko et al: Chem. Pharm. Bull. 28, 2507 (1980)].
We have found that if the TP5 chain is shortened starting from the C-terminal moiety and not from the N-terminal moiety as suggested by the Japanese authors [Abiko et al: Chem. Pharm. Bull. 28, 2507 (1980)], the Arg-Lys-Asp-Val tetrapeptide and even the Arg-Lys-Asp tripeptide is active, i.e. increases the number of the lymphocytes forming the E-rosette.